title: Acetylcholinesterase inhibition by (+)physostigmine and efficacy against lethality induced by soman.
abstract: The optical isomer (+)Physostigmine [(+)Phy] is a very weak anticholinesterase. In a recent report, pretreatment with (+)Phy, at a dose which failed to inhibit acetylcholinesterase (AChE), and atropine provided efficacy against a lethal dose of sarin (SYNAPSE:2, 139, 1988). It was of interest to see whether (+)Phy could protect against soman at a dose which caused only marginal inhibition of the whole blood (WB) AChE in guinea pigs (GPs). (-)Phy (0.15 mg/kg, im) and (+)Phy (10.0 mg/kg, im) produced nearly 70% inhibition of WB AChE at 30 min whereas (+)Phy (0.15 mg/kg, im) caused only marginal inhibition. Groups of guinea pigs (20/group) were dosed, im, with (-)Phy (0.15 mg/kg), (+)Phy (0.15 mg/kg), (+)Phy (10.0 mg/kg) or vehicle (0.5 ml/kg) respectively in one thigh while the mild anticholinergic trihexyphenidyl (THP), 2.0 mg/kg, was injected into the other thigh of 10 animals from each of the respective groups. Thirty min after pretreatment, all animals were challenged with soman (60 micrograms/kg, sc; 2 LD50s); this dose of soman is lethal in unprotected animals. (-)Phy or (+)Phy (10 mg/kg) alone protected nearly 50% from soman lethality, and in combination with THP, all animals survived. In contrast, (+)Phy (0.15 mg/kg; alone or together with THP) was completely ineffective against a 2 LD50 challenge of soman. These data support the hypothesis that protection against soman-induced lethality is related to the degree of carbamylation of the AChE just prior to challenge.
authors.affiliation: U.S. Army Medical Research Institute for Chemical Defense, Aberdeen Proving Ground, MD 21010-5425.
authors.forename: L W
authors.initials: LW
authors.lastname: Harris
authors.forename: D R
authors.initials: DR
authors.lastname: Anderson
authors.forename: A M
authors.initials: AM
authors.lastname: Pastelak
authors.forename: B
authors.initials: B
authors.lastname: Vanderpool
mesh_terms: D000110:Acetylcholinesterase / Q000097:blood / Q000378:metabolism; D000818:Animals; D002800:Cholinesterase Inhibitors / Q000494:pharmacology*; D005260:Female; D006168:Guinea Pigs; D008297:Male; D010830:Physostigmine / Q000494:pharmacology*; D012999:Soman / Q000633:toxicity*; D013237:Stereoisomerism; D014282:Trihexyphenidyl / Q000494:pharmacology
chemical_list: D002800:Cholinesterase Inhibitors; D014282:Trihexyphenidyl; D012999:Soman; D010830:Physostigmine; D000110:Acetylcholinesterase